Study to Evaluate the Efficacy and Safety of Hydrocodone Bitartrate Extended-Release Tablets (CEP-33237) for Relief of Moderate to Severe Pain in Patients With Osteoarthritis or Low Back Pain Who Require Opioid Treatment for an Extended Period of Time

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01240863
• Collaborator: (none)
• Enrollment: 391
• Locations: 73
• Arms: 2
• Duration (Months): 9
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate efficacy of hydrocodone extended-release (ER) tablets compared with placebo in alleviating moderate to severe pain in patients with osteoarthritis or low back pain as assessed by the weekly Average Pain Intensity (API) at week 12.

Condition or Disease	Intervention/Treatment	Phase
Chronic Pain	Drug: Hydrocodone ER; Drug: Placebo	Phase 3

Detailed Description

The study consisted of a screening period of approximately 7 to 14 days, an open label titration period of up to 6 weeks, and a double blind treatment period of 12 weeks.

Participants entered the open label titration period and received hydrocodone ER tablets beginning with 15 mg every 12 hours for 3 to 7 days. The objective of the open label titration period was to find the successful dose of hydrocodone ER tablets that produced stable pain relief (defined as an Average Pain Intensity (API) score of 4 or less on the 11-point numerical rating scale for either 3 consecutive days or 3 out of 5 consecutive days while the patient was maintained on the same dose of study drug for up to 7 days). Patients returned to the study center prior to each dose adjustment.

Participants who met the criterion of a stabilized dose were randomly assigned into the 12 week, double blind, placebo controlled treatment period on the final day of the open label titration period (baseline visit). Patients began treatment with double blind study drug at the effective dose of hydrocodone ER tablets achieved during the titration period or matching placebo. Rescue medication was permitted in addition to the study drug during the double blind treatment period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 391 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Hydrocodone Bitartrate Extended-Release Tablets (CEP-33237) at 15 to 90 mg Every 12 Hours for Relief of Moderate to Severe Pain in Patients With Osteoarthritis or Low Back Pain Who Require Opioid Treatment for an Extended Period of Time
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain during the titration period. During the treatment period, participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step-wise, double-blind schedule to tamper off active drug was implemented during the first 2 weeks of the 12-week, double-blind, placebo-controlled treatment period to reduce the risk of withdrawal effects in participants randomly assigned to placebo.	Drug: Hydrocodone ER; During the open-label, titration period, all participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours to identify a dosage deemed successful for managing their pain. Hydrocodone ER was taken by participants randomized to the hydrocodone ER treatment arm during the double-blind treatment period at the dose level identified during the titration period. Participants were instructed to take tablets with a glass of water on an empty stomach at least 1 hour before or 2 hours after eating.; Other Names: CEP-33237 Hydrocodone bitartrate extended-release ; Drug: Placebo; Placebo matching the active drug dose identified during the titration period was taken by participants randomized to the placebo treatment arm during the double-blind treatment period. Participants were instructed to take intervention with a glass of water on an empty stomach at least 1 hour before or 2 hours after eating.
Experimental: Hydrocodone ER Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain during the titration period. During the 12-week, double-blind, placebo-controlled treatment period, participants randomly assigned to hydrocodone ER were administered tablets every 12 hours at the dosage deemed successful for managing their pain during the titration period.	Drug: Hydrocodone ER; During the open-label, titration period, all participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours to identify a dosage deemed successful for managing their pain. Hydrocodone ER was taken by participants randomized to the hydrocodone ER treatment arm during the double-blind treatment period at the dose level identified during the titration period. Participants were instructed to take tablets with a glass of water on an empty stomach at least 1 hour before or 2 hours after eating.; Other Names: CEP-33237 Hydrocodone bitartrate extended-release

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 12 in Weekly Average Pain Intensity (wAPI) [Baseline (end of Open-Label Titration Period), Week 12 of Double-blind Treatment Period]

   The primary efficacy variable was the change from baseline to week 12 in the wAPI. The API over the previous 24 hours, based on the 11-point Numerical Rating Scale (NRS 11), was collected daily by e-diary. The Week 12 wAPI scores from the previous 7 days were calculated for each study visit and averaged. The baseline wAPI score was calculated by averaging API scores from 3 to 12 days when the successful dose of hydrocodone extended release was confirmed at the end of the open label titration period, before patients were randomly assigned study drug. In the case of missing week-12 data due to early withdrawal from the study, or excessive rescue medication usage, the wAPI for week 12 was imputed. The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain on a Likert-type scale in which 0 is no pain and 10 is the worst pain imaginable. Negative change from baseline values indicate lessening in pain intensity.

Secondary Outcome Measures

1. Percentage of Participants Withdrawn From the Study During the Double-Blind Treatment Period By Reason [Day 1 to Week 12 of the double-blind treatment period]

   Percentage of participants who withdrew from the study during the double-blind treatment period. Withdrawal is due to any cause, including lack of efficacy.

2. Kaplan-Meier Estimates for Time to Discontinuation From the Study [Day 1 to Week 12 of the double-blind treatment period]

   Kaplan-Meier estimates for time to discontinuation from the study (due to any cause) was calculated as the number of days since participants were randomly assigned to study drug treatment, ie, the difference between the date the participants withdrew and the date participants were randomly assigned to study drug treatment. The censoring flag was set to 0 if a participant was withdrawn from study drug treatment early and was set to 1 if the participant completed the 12 week treatment period. Censoring time was calculated as the difference of treatment completion date (ie, date of last study drug administration) and date participant was randomly assigned to study drug treatment.

3. Participants With a Weekly Average Pain Intensity (wAPI) Increase From Baseline Exceeding 33% [Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, and 12 of the Double-blind treatment period]

   The API over the previous 24 hours, based on the 11-point Numerical Rating Scale (NRS 11), was collected daily by e-diary. The wAPI scores from the previous 7 days were calculated for each study visit and averaged. The baseline wAPI score was calculated by averaging API scores from 3 to 12 days when the successful dose of hydrocodone extended release was confirmed at the end of the open label titration period, before patients were randomly assigned study drug. The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain on a Likert-type scale in which 0 is no pain and 10 is the worst pain imaginable.

4. Participants With a Weekly Average Pain Intensity (wAPI) Increase From Baseline Exceeding 50% [Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, and 12 of the Double-blind treatment period]

   The API over the previous 24 hours, based on the 11-point Numerical Rating Scale (NRS 11), was collected daily by e-diary. The wAPI scores from the previous 7 days were calculated for each study visit and averaged. The baseline wAPI score was calculated by averaging API scores from 3 to 12 days when the successful dose of hydrocodone extended release was confirmed at the end of the open label titration period, before patients were randomly assigned study drug. The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain on a Likert-type scale in which 0 is no pain and 10 is the worst pain imaginable.

5. Weekly Average Pain Intensity (wAPI) Scores During the Double-blind Treatment Period [Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, and 12 of the Double-blind treatment period]

   The API over the previous 24 hours, based on the 11-point Numerical Rating Scale (NRS 11), was collected daily by e-diary. The wAPI scores from the previous 7 days were calculated for each study visit and averaged. The baseline wAPI score was calculated by averaging API scores from 3 to 12 days when the successful dose of hydrocodone extended release was confirmed at the end of the open label titration period, before patients were randomly assigned study drug. The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain on a Likert-type scale in which 0 is no pain and 10 is the worst pain imaginable.

6. Weekly Average Worst Pain Intensity (WPI) Scores During the Double-blind Treatment Period [Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, and 12 of the Double-blind treatment period]

   The WPI was recorded by the patient in the e-diary daily throughout the study, based on the Numeric Rating Scale (NRS-11). Participants were asked to select the number that best described their WPI over the previous 24 hours. Values were averaged for each week. The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain on a Likert-type scale in which 0 is no pain and 10 is the worst pain imaginable.

7. Clinician Assessment of Patient Function (CAPF) at Week 4 [Week 4 of the Double-blind Treatment Period]

   Clinicians assessed participants across 5 dimensions: Patients general activities Patients walking ability Patients ability to work/perform activities of daily living Patients relationships with others Patients enjoyment of life Assessments are rated on a 7-point scale, in which 1 is very much worsened and 7 is very much improved since the start of the study.

8. Clinician Assessment of Patient Function (CAPF) at Week 8 [Week 8 of the Double-blind Treatment Period]

   Clinicians assessed participants across 5 dimensions: Patients general activities Patients walking ability Patients ability to work/perform activities of daily living Patients relationships with others Patients enjoyment of life Assessments are rated on a 7-point scale, in which 1 is very much worsened and 7 is very much improved since the start of the study.

9. Clinician Assessment of Patient Function (CAPF) at Week 12 [Week 12 of the Double-blind Treatment Period]

   Clinicians assessed participants across 5 dimensions: Patients general activities Patients walking ability Patients ability to work/perform activities of daily living Patients relationships with others Patients enjoyment of life Assessments are rated on a 7-point scale, in which 1 is very much worsened and 7 is very much improved since the start of the study.

10. Clinician Assessment of Patient Function (CAPF) at Endpoint [Endpoint of the Double-blind Treatment Period (up to week 12)]

    Clinicians assessed participants across 5 dimensions: Patients general activities Patients walking ability Patients ability to work/perform activities of daily living Patients relationships with others Patients enjoyment of life Assessments are rated on a 7-point scale, in which 1 is very much worsened and 7 is very much improved since the start of the study. Endpoint values are the last observed postbaseline data.

11. Patient Assessment of Function (PAF) at Week 4 [Week 4 of the Double-blind Treatment Period]

    The PAF is a self-administered questionnaire used to measure patients' assessment of their own ability to function in normal activities. Answers to the 7 questions were rated on a 7 point scale in which 1 was very much worsened and 7 were very much improved since the start of the study. The seven functional areas are: ability to go to work ability to perform at work (includes both work outside the home and housework) ability to walk ability to exercise ability to participate in social events ability to have sex ability to enjoy life

12. Patient Assessment of Function (PAF) at Week 8 [Week 8 of the Double-blind Treatment Period]

    The PAF is a self-administered questionnaire used to measure patients' assessment of their own ability to function in normal activities. Answers to the 7 questions were rated on a 7 point scale in which 1 was very much worsened and 7 were very much improved since the start of the study. The seven functional areas are: ability to go to work ability to perform at work (includes both work outside the home and housework) ability to walk ability to exercise ability to participate in social events ability to have sex ability to enjoy life

13. Patient Assessment of Function (PAF) at Week 12 [Week 12 of the Double-blind Treatment Period]

    The PAF is a self-administered questionnaire used to measure patients' assessment of their own ability to function in normal activities. Answers to the 7 questions were rated on a 7 point scale in which 1 was very much worsened and 7 were very much improved since the start of the study. The seven functional areas are: ability to go to work ability to perform at work (includes both work outside the home and housework) ability to walk ability to exercise ability to participate in social events ability to have sex ability to enjoy life

14. Patient Assessment of Function (PAF) at Endpoint [Endpoint of the Double-blind Treatment Period (up to week 12)]

    The PAF is a self-administered questionnaire used to measure patients' assessment of their own ability to function in normal activities. Answers to the 7 questions were rated on a 7 point scale in which 1 was very much worsened and 7 were very much improved since the start of the study. The seven functional areas are: ability to go to work ability to perform at work (includes both work outside the home and housework) ability to walk ability to exercise ability to participate in social events ability to have sex ability to enjoy life Endpoint values are the last observed postbaseline data.

15. Clinician Global Impression of Severity (CGI-S) of Illness Scores During the Double-blind Treatment Period [Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, and 12 of the Double-blind treatment period]

    The CGI-S is a clinician-rated scale that assesses the severity of the patient's pain condition and response to the treatment. Severity of illness, as related to moderate to severe pain, consists of the following 7 categories: 1 normal-shows no sign of illness, 2 borderline ill, 3 mildly (slightly) ill, 4 moderately ill, 5 markedly ill, 6 severely ill, and 7 among the most extremely ill (Guy 1976). The clinician assesses the severity of the patient's condition, based on the clinician's total clinical experience with patients with this condition, in response to treatment. Endpoint values are the last observed postbaseline data.

16. Short-Form Health Survey (SF-36) Physical and Mental Component Summary Scores at Baseline, Week 12 and Endpoint [Baseline (end of Open-Label Titration Period), Week 12 and Endpoint (last visit up to week 12) of the Double-blind treatment period]

    SF-36 is a generic 36-item questionnaire measuring health-related quality of life (HRQL) covering 2 summary measures: physical component summary (PCS) and mental component summary (MCS). The SF-36 consists of 8 subscales. The PCS is represented by 4 subscales: physical function, role limitations due to physical problems, pain, and general health perception. The MCS is represented by 4 subscales: vitality, social function, role limitations due to emotional problems, and mental health. Participants self-report on items in a subscale that have between 2-6 choices per item using Likert-type responses (e.g. none of the time, some of the time, etc.). PCS and MCS scores are constructed as a T-score with a mean of 50 and standard deviation of 10 and no minimum or maximum score; higher scores indicate better health status.

17. Brief Pain Inventory - Short Form (BPI-SF) Pain Interference Mean Score During the Double-Blind Treatment Period [Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, 12 and Endpoint (last visit up to week 12) of the Double-blind treatment period]

    For pain interference, the BPI-SF used numerical scales to measure how much pain had interfered with 7 daily activities, including general activity, walking, work, mood, enjoyment of life, relations with others, and sleep in the past 24 hours. The scale used an 11 point Likert scale; range: 0 [does not interfere] to 10 [completely interferes]. BPI pain interference was typically scored as the mean of the 7 interference items. This mean could be used if at least 4 of 7 items had been completed on a given administration.

18. Participants With Adverse Events [Day 1 up to Day 52 in Open-Label Titration; Day 1 up to Day 128 in Double-Blind Treatment period]

    An adverse event (AE) was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

19. Participants With Potentially Clinically Significant Abnormal Vital Signs Values During the Double-Blind Treatment Period [Day 1 up to Day 128 in Double-Blind Treatment period]

    Data represents participants with potentially clinically significant (PCS) vital sign values. Significance criteria Pulse - high: >=120 and increase of >= 15 beats/minute from baseline Pulse - low: <=50 and decrease of >=15 beats/minute Systolic blood pressure - high: >=180 and increase >=20 mmHg Systolic blood pressure - low: <=90 and decrease >=20 mmHg Diastolic blood pressure - high: >=105 and increase of >=15 mmHg Diastolic blood pressure - low: <=50 and decrease of >=15 mmHg

20. Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period [Day 1 up to Day 128 in Double-Blind Treatment period]

    Data represents participants with potentially clinically significant abnormal serum chemistry, hematology and urinalysis values. Significance criteria: Blood urea nitrogen: >=10.71 mmol/L Uric acid: M>=625, F>=506 μmol/L Hemoglobin: M<=115, F<=95 g/dL Hematocrit: M<0.37, F<0.32 % Urinalysis: blood (hemoglobin) and total protein: >=2 unit increase from baseline

21. Subjective Opiate Withdrawal Scales (SOWS) Scores During the Double-Blind Treatment Period [Weeks 1, 2, 4, 8, 12 and Endpoint (last visit up to Week 12) of the Double-blind treatment period]

    The results of the SOWS were collected in the e-diary daily during the first 4 weeks of the double blind treatment period and then during clinic visits at weeks 8 and 12 or early termination. The SOWS was a self administered questionnaire used to measure a participant's signs and symptoms of withdrawal from opiates. The scale contained 16 symptoms (eg, my nose is running; I feel restless), the participant rated the intensity on a scale of 0 (not at all) to 4 (extremely) for a total score of 0-64. The daily total score for the first 4 weeks was the largest score observed during the time period preceding that visit. For example, the week 1 score for each participant was the largest total score on any day between baseline and the night before the week 1 visit; the week 4 score for each participant was the largest score observed between the week 2 visit and the night before the week 4 visit.

22. Clinical Opiate Withdrawal Scales (COWS) Scores During the Double-Blind Treatment Period [Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, 12 and Endpoint (last visit up to Week 12) of the Double-blind treatment period]

    The COWS was a clinician rated scale used to measure a participant's signs and symptoms of withdrawal from opiates, with ratings based only on apparent relationship to withdrawal. The COWS was performed at day 0 and weeks 1, 2, 4, 8, and 12 (double blind treatment period) or early termination. The scale contained 11 signs/symptoms whose intensity the clinician rated on a scale of 0 to 4 or 5. A total score was calculated as the sum of the responses to the 11 signs/symptoms for a total range of 0-48. Withdrawal severity was classified, based on the total score, as follows: 0 to 4=normal 5 to 12=mild 13 to 24=moderate 25 to 36=moderately severe >36=severe

23. Addiction Behavior Checklist (ABC) Total Scores During Both the Open-Label Titration and Double-Blind Treatment Periods [Baseline for Open-Label Titration period, Baseline for Double-Blind Treatment period (which is also the end of the Open-Label Titration period), Weeks 1, 4, 8, 12, and Endpoint (last visit up to Week 12) of the Double-blind Treatment period]

    The ABC was a clinician rated scale that consisted of a brief (20 item) questionnaire designed to track behaviors characteristic of addiction related to prescription opioid medications in chronic pain populations. Items were focused on observable behaviors noted both during and between clinic visits. Each affirmative response was counted as one point, and points were added to calculate the total score, consequently resulting in scores ranging from 0 to 20 (0=no addiction-related behaviors seen and higher scores indicating an increasing number of addition-related behaviors seen). The ABC was to be performed at visits 2 and 7 (beginning and end of Open-label Titration period) and weeks 1, 4, 8, and 12 (Double-blind Treatment period) or early termination.

24. Current Opioid Misuse Measures (COMM) Total Scores During Both the Open-Label Titration and Double-Blind Treatment Periods [Baseline for Open-Label Titration period, Baseline for Double-Blind Treatment period (which is also the end of the Open-Label Titration period), Weeks 1, 4, 8, 12, and Endpoint (last visit up to Week 12) of the Double-blind Treatment period]

    The COMM was a clinician rated scale developed as a brief self report measure of current aberrant drug-related behavior for patients with chronic pain who were already on long term opioid therapy. A total score was calculated as the sum of the 17 questions. The total score ranged from 0 to 68. A score of 0 indicates no aberrant drug-related behaviors were seen. Patients with a total score of 9 or greater were classified as exhibiting aberrant drug-related behavior. The COMM was to be performed at visits 2 and 7 (beginning and end of Open-label Titration period) and weeks 1, 4, 8, and 12 (Double-blind Treatment period) or early termination.

25. Change From Baseline to Endpoint in the Double-Blind Treatment Phase in Electrocardiogram (ECG) Parameters [Baseline (end of Open-Label Titration Period), Endpoint (last visit up to Week 12) of the Double-blind treatment period]

    A 12-lead ECG was conducted at baseline and the last visit during the double-blind treatment period (week 12, or early termination).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The patient is able to speak English and is willing to provide written informed consent, including a written opioid agreement, to participate in this study.

• The patient must be willing and able to successfully self-administer the study drug, comply with study restrictions, complete the electronic diary, and return to the clinic for scheduled study visits as specified in this protocol.

• Women of childbearing potential (not surgically sterile or 2 years postmenopausal), must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after participation in the study, and have a negative pregnancy test at screening.

• The patient has pain of at least 3 months' duration associated with osteoarthritis or low back pain.

• The patient reports an average pain intensity score, over the prior 24 hours, of 5 or more on the 11-point numerical rating scale.

• If the patient is receiving physical therapy, biofeedback therapy, acupuncture therapy, or herbal remedies, these therapies must remain unchanged during the study.

• The patient must not participate in other study involving an investigational agent while enrolled into the present study.

Exclusion Criteria:

• The patient has known or suspected hypersensitivities, allergies, or other contraindications to any ingredient in the study drug.

• The patient has a recent history (within 5 years) or current evidence of alcohol or other substance abuse with the exception of nicotine or caffeine.

• The patient has medical or psychiatric disease that, in the opinion of the investigator, would compromise collected data.

• The patient is taking a total (ie, around-the-clock plus rescue medication) of more than 135 mg/day of oxycodone, or equivalent, during the 14 days prior to screening.

• The patient has a history of suicidality.

• The patient is expected to have surgery during the study.

• The patient's primary painful condition under study is related to any source of chronic pain other than osteoarthritis or low back pain.

• The patient is pregnant or lactating.

• The patient has active malignancy.

• The patient has human immunodeficiency virus (HIV).

• In the judgment of the investigator, the patient has any clinically significant deviation from normal in the physical examination and/or clinical laboratory test values.

• The patient has cardiopulmonary disease that would, in the opinion of the investigator, significantly increase the risk of treatment with opioids.

• The patient has participated in a study involving an investigational drug in the previous 30 days.

• The patient has received a monoamine oxidase inhibitor (MAOI) within 14 days before the first treatment with study drug.

• The patient has any other medical condition or is receiving concomitant medication/therapy (e.g., regional nerve block) that would, in the opinion of the investigator, compromise the patient's safety or compliance with the study protocol, or compromise collected data.

• The patient is involved in active litigation in regard to the pain currently being treated.

• The patient has a positive urine drug screen (UDS) that is not medically explainable.

• The investigator feels that the patient is not suitable for the study for any reason.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Horizon Research Group LLC	Mobile	Alabama	United States	36608
2	Radiant Research, Inc.	Chandler	Arizona	United States	85225
3	Radiant Research, Inc.	Scottsdale	Arizona	United States	85251
4	Radiant Research Inc.	Tucson	Arizona	United States	85710
5	Physician Alliance Research Center	Anaheim	California	United States	92804
6	Associated Pharmaceutical Research Center, Inc.	Buena Park	California	United States	90620
7	Providence Clinical Research	Burbank	California	United States	91505
8	Synergy Clinical Research	Escondido	California	United States	92025
9	Research Center of Fresno, Inc.	Fresno	California	United States	93726
10	Pacific Coast Pain Management Center	Laguna Hills	California	United States	92637
11	South Orange County Surgical Medical Group	Laguna Hills	California	United States	92653
12	Robert M. Karns, MD A Medical Corporation	Los Angeles	California	United States	90036
13	Accelovance, Inc.	San Diego	California	United States	92108
14	Radiant Research, Inc.	Santa Rosa	California	United States	95405
15	Bayview Research Group, LLC	Valley Village	California	United States	91607
16	Radiant Research, Inc	Denver	Colorado	United States	80239
17	Clinical Research of West Florida, Inc.	Clearwater	Florida	United States	33765
18	Avail Clinical Research, LLC	DeLand	Florida	United States	32720
19	International Research Associates, LLC	Miami	Florida	United States	33183
20	Compass Research	Orlando	Florida	United States	32806
21	Radiant Research, Inc.	Pinellas Park	Florida	United States	33781
22	Gold Coast Research LLC	Plantation	Florida	United States	33317
23	Sarasota Pain Medicine Research LLC	Sarasota	Florida	United States	34238
24	Clinical Research of West Florida, Inc.	Tampa	Florida	United States	33603
25	Drug Studies America	Marietta	Georgia	United States	30060
26	Georgia Institute for Clinical Research, LLC	Marietta	Georgia	United States	30060
27	Better Health Clinical Research, Inc.	Newnan	Georgia	United States	30265
28	Millennium Pain Center	Bloomington	Illinois	United States	61701
29	Medex Healthcare Research, Inc.	Chicago	Illinois	United States	60603
30	Rehabilitation Associates of Indiana	Indianapolis	Indiana	United States	46250
31	International Clinical Research, Inc.	Leawood	Kansas	United States	66211
32	Community Research	Crestview	Kentucky	United States	41017
33	The Pain Treatment Center of the Bluegrass	Lexington	Kentucky	United States	40503
34	Horizon Research Group, LLC	Baton Rouge	Louisiana	United States	70809
35	WK River Cities Clinical Research Center	Shreveport	Louisiana	United States	71105
36	MidAtlantic Pain Medicine Center	Pikesville	Maryland	United States	21208
37	Beacon Clinical Research, LLC	Brockton	Massachusetts	United States	02301
38	HealthCare Research	Florissant	Missouri	United States	63031
39	Medex Healthcare Research Inc.	Saint Louis	Missouri	United States	63117
40	Sundance Clinical Research, LLC	Saint Louis	Missouri	United States	63141
41	Meridian Clinical Research	Omaha	Nebraska	United States	68134
42	Clinical Research Center of Nevada	Las Vegas	Nevada	United States	89104
43	Advanced Pain Consultants	Voorhees	New Jersey	United States	08043
44	Upstate Clinical Research Associates	Williamsville	New York	United States	14221
45	Wake Research Associates	Raleigh	North Carolina	United States	27612
46	Radiant Research, Inc	Akron	Ohio	United States	44311
47	Sterling Research Group, Ltd.	Cincinnati	Ohio	United States	45219
48	Community Research, Inc	Cincinnati	Ohio	United States	45227
49	Community Research, Inc	Cincinnati	Ohio	United States	45245
50	Rapid Medical Research	Cleveland	Ohio	United States	44122
51	Columbus Clinical Research	Columbus	Ohio	United States	43213
52	SP Research	Oklahoma City	Oklahoma	United States	73112
53	Pain Research of Oregon	Eugene	Oregon	United States	97401
54	Summit Research Network Inc.	Portland	Oregon	United States	97210
55	Brandywine Clinical Research	Downingtown	Pennsylvania	United States	19335
56	Tipton Medical and Diagnostic Center	Tipton	Pennsylvania	United States	16684
57	AMH Feasterville Family Health Care Center	Trevose	Pennsylvania	United States	19053
58	Clinical Research Center of Reading	Wyomissing	Pennsylvania	United States	19610
59	Omega Medical Research	Warwick	Rhode Island	United States	02886
60	Radiant Research Inc.	Anderson	South Carolina	United States	29621
61	Greenville Pharmaceutical Research	Greenville	South Carolina	United States	29615
62	Radiant Research, Inc	Greer	South Carolina	United States	29651
63	Trident Institute of Medical Research, LLC	North Charleston	South Carolina	United States	29406
64	South Carolina Pharmaceutical Research	Spartanburg	South Carolina	United States	29303
65	KRK Medical Research	Dallas	Texas	United States	75230
66	Radiant Research Dallas	Dallas	Texas	United States	75231
67	Renaissance Clinical Research & Hypertension of Texas, PLLC	Dallas	Texas	United States	75235
68	Medstar Clinical Research	Houston	Texas	United States	77083
69	Benchmark Research	San Angelo	Texas	United States	76904
70	DCT-Sugarland, LLC	Sugar Land	Texas	United States	77478
71	Hillcrest Family Health Centers	Waco	Texas	United States	76710
72	Aspen Clinical Research, LLC	Orem	Utah	United States	84058
73	Lifetree Clinical Research	Salt Lake City	Utah	United States	84106

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Sponsor's Medical Expert, MD, Cephalon

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT01240863
• Other Study ID Numbers: C33237/3079
• First Posted: Nov 15, 2010
• Last Update Posted: Jun 5, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: osteoarthritis; low back pain; Moderate to Severe Pain
• Additional relevant MeSH terms: Osteoarthritis; Back Pain; Low Back Pain; Chronic Pain; Hydrocodone

Study Results

Participant Flow

Recruitment Details	A total of 519 patients with osteoarthritis or low back pain were screened for enrollment into the study; of these, 391 patients at 71 centers in the US met entry criteria and were enrolled into the titration period of the study.
Pre-assignment Detail	Of the 389 patients enrolled and treated during the titration period, 294 (75%) patients identified a successful dose and therefore completed the open-label titration period, and were randomly assigned to receive hydrocodone extended-release (ER) tablets (146 patients) or placebo (148 patients) in the double-blind treatment period.

Arm/Group Title	Hydrocodone ER (Open-Label Titration Period)	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	All enrolled participants entered the open label titration period and received hydrocodone extended release (ER) tablets beginning with 15 mg every 12 hours for 3 to 7 days. Dosages were titrated upward until pain was effectively controlled. If an effective dosage between 15 mg - 90 mg twice a day was not identified within 6 week, the participant was withdrawn.	Participants were administered placebo tablets twice a day that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Period Title: Open-label Titration Period
STARTED	391	0	0
Safety Analysis Set	389	0	0
COMPLETED	294	0	0
NOT COMPLETED	97	0	0
Period Title: Open-label Titration Period
STARTED	0	148	146
Full Analysis and Safety Analysis Sets	0	147	146
COMPLETED	0	102	94
NOT COMPLETED	0	46	52

Baseline Characteristics

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)	Total
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.	Total of all reporting groups
Overall Participants	148	146	294
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.7 (12.09)	53.6 (10.38)	53.1 (11.26)
Sex: Female, Male (Count of Participants)
Female	88 59.5%	87 59.6%	175 59.5%
Male	60 40.5%	59 40.4%	119 40.5%
Race/Ethnicity, Customized (Count of Participants)
White	105 70.9%	115 78.8%	220 74.8%
Black	41 27.7%	28 19.2%	69 23.5%
Other	2 1.4%	3 2.1%	5 1.7%
Asian	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	3 2%	9 6.2%	12 4.1%
Non-Hispanic and non-Latino	144 97.3%	137 93.8%	281 95.6%
Unknown	1 0.7%	0 0%	1 0.3%
Age group (Count of Participants)
<=65 years	133 89.9%	126 86.3%	259 88.1%
>65 years	15 10.1%	20 13.7%	35 11.9%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	32.8 (7.33)	33.0 (8.16)	32.9 (7.74)
Type of Pain (Count of Participants)
Low back pain	107 72.3%	104 71.2%	211 71.8%
Osteoarthritis	41 27.7%	42 28.8%	83 28.2%
Duration since Diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.5 (9.06)	12.1 (9.97)	12.3 (9.51)
Participants on Opioid Therapy (Count of Participants)
On opioid therapy	103 69.6%	100 68.5%	203 69%
Not on opioid therapy	45 30.4%	46 31.5%	91 31%
Duration of Opioid Therapy (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.1 (4.90)	3.9 (4.76)	4.0 (4.82)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 12 in Weekly Average Pain Intensity (wAPI)
Description	The primary efficacy variable was the change from baseline to week 12 in the wAPI. The API over the previous 24 hours, based on the 11-point Numerical Rating Scale (NRS 11), was collected daily by e-diary. The Week 12 wAPI scores from the previous 7 days were calculated for each study visit and averaged. The baseline wAPI score was calculated by averaging API scores from 3 to 12 days when the successful dose of hydrocodone extended release was confirmed at the end of the open label titration period, before patients were randomly assigned study drug. In the case of missing week-12 data due to early withdrawal from the study, or excessive rescue medication usage, the wAPI for week 12 was imputed. The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain on a Likert-type scale in which 0 is no pain and 10 is the worst pain imaginable. Negative change from baseline values indicate lessening in pain intensity.
Time Frame	Baseline (end of Open-Label Titration Period), Week 12 of Double-blind Treatment Period

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS). One placebo patient was withdrawn from the study prior to receiving drug in the Double-blind Treatment period and is not included in the FAS. In the case of missing week-12 data due to early withdrawal from the study, or excessive rescue medication usage, the wAPI for week 12 was imputed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Least Squares Mean (Standard Error) [units on a scale]	0.14 (0.169)	-0.22 (0.176)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Double-blind Treatment Period), Hydrocodone ER (Double-blind Treatment Period)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.134
	Comments	statistical significance level of 0.05.
	Method	ANCOVA
	Comments	Treatment and stratification (opioid naïve/opioid experienced) factors as the fixed effects; screening and baseline APIs as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	placebo - hydrocodone

2. Secondary Outcome

Title	Percentage of Participants Withdrawn From the Study During the Double-Blind Treatment Period By Reason
Description	Percentage of participants who withdrew from the study during the double-blind treatment period. Withdrawal is due to any cause, including lack of efficacy.
Time Frame	Day 1 to Week 12 of the double-blind treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Total withdrawn from study period	31 20.9%	36 24.7%
Lack of efficacy	12 8.1%	3 2.1%
Adverse event	3 2%	7 4.8%
Consent withdrawn	2 1.4%	3 2.1%
Lost to follow-up	0 0%	0 0%
Protocol violation	6 4.1%	10 6.8%
Noncompliance to study procedures	1 0.7%	1 0.7%
Noncompliance to study drug admin	6 4.1%	8 5.5%
Other	1 0.7%	3 2.1%

3. Secondary Outcome

Title	Kaplan-Meier Estimates for Time to Discontinuation From the Study
Description	Kaplan-Meier estimates for time to discontinuation from the study (due to any cause) was calculated as the number of days since participants were randomly assigned to study drug treatment, ie, the difference between the date the participants withdrew and the date participants were randomly assigned to study drug treatment. The censoring flag was set to 0 if a participant was withdrawn from study drug treatment early and was set to 1 if the participant completed the 12 week treatment period. Censoring time was calculated as the difference of treatment completion date (ie, date of last study drug administration) and date participant was randomly assigned to study drug treatment.
Time Frame	Day 1 to Week 12 of the double-blind treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Median (Inter-Quartile Range) [days]	99	NA

4. Secondary Outcome

Title	Participants With a Weekly Average Pain Intensity (wAPI) Increase From Baseline Exceeding 33%
Description	The API over the previous 24 hours, based on the 11-point Numerical Rating Scale (NRS 11), was collected daily by e-diary. The wAPI scores from the previous 7 days were calculated for each study visit and averaged. The baseline wAPI score was calculated by averaging API scores from 3 to 12 days when the successful dose of hydrocodone extended release was confirmed at the end of the open label titration period, before patients were randomly assigned study drug. The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain on a Likert-type scale in which 0 is no pain and 10 is the worst pain imaginable.
Time Frame	Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, and 12 of the Double-blind treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Week 1	14 9.5%	13 8.9%
Week 2	31 20.9%	15 10.3%
Week 4	32 21.6%	17 11.6%
Week 8	26 17.6%	9 6.2%
Week 12	24 16.2%	11 7.5%

5. Secondary Outcome

Title	Participants With a Weekly Average Pain Intensity (wAPI) Increase From Baseline Exceeding 50%
Description	The API over the previous 24 hours, based on the 11-point Numerical Rating Scale (NRS 11), was collected daily by e-diary. The wAPI scores from the previous 7 days were calculated for each study visit and averaged. The baseline wAPI score was calculated by averaging API scores from 3 to 12 days when the successful dose of hydrocodone extended release was confirmed at the end of the open label titration period, before patients were randomly assigned study drug. The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain on a Likert-type scale in which 0 is no pain and 10 is the worst pain imaginable.
Time Frame	Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, and 12 of the Double-blind treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Week 1	7 4.7%	9 6.2%
Week 2	16 10.8%	9 6.2%
Week 4	19 12.8%	9 6.2%
Week 8	20 13.5%	6 4.1%
Week 12	15 10.1%	6 4.1%

6. Secondary Outcome

Title	Weekly Average Pain Intensity (wAPI) Scores During the Double-blind Treatment Period
Description	The API over the previous 24 hours, based on the 11-point Numerical Rating Scale (NRS 11), was collected daily by e-diary. The wAPI scores from the previous 7 days were calculated for each study visit and averaged. The baseline wAPI score was calculated by averaging API scores from 3 to 12 days when the successful dose of hydrocodone extended release was confirmed at the end of the open label titration period, before patients were randomly assigned study drug. The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain on a Likert-type scale in which 0 is no pain and 10 is the worst pain imaginable.
Time Frame	Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, and 12 of the Double-blind treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Baseline	3.75 (0.903)	3.79 (0.981)
Week 1	3.73 (1.319)	3.67 (1.291)
Week 2	3.89 (1.498)	3.58 (1.433)
Week 4	3.78 (1.702)	3.48 (1.447)
Week 8	3.68 (1.823)	3.16 (1.461)
Week 12	3.61 (1.783)	3.30 (1.638)

7. Secondary Outcome

Title	Weekly Average Worst Pain Intensity (WPI) Scores During the Double-blind Treatment Period
Description	The WPI was recorded by the patient in the e-diary daily throughout the study, based on the Numeric Rating Scale (NRS-11). Participants were asked to select the number that best described their WPI over the previous 24 hours. Values were averaged for each week. The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain on a Likert-type scale in which 0 is no pain and 10 is the worst pain imaginable.
Time Frame	Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, and 12 of the Double-blind treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Baseline	4.75 (1.369)	4.85 (1.265)
Week 1	4.79 (1.776)	4.79 (1.636)
Week 2	5.02 (1.951)	4.65 (1.781)
Week 4	4.77 (2.099)	4.55 (1.832)
Week 8	4.57 (2.228)	4.18 (1.892)
Week 12	4.57 (2.210)	4.22 (1.873)

8. Secondary Outcome

Title	Clinician Assessment of Patient Function (CAPF) at Week 4
Description	Clinicians assessed participants across 5 dimensions: Patients general activities Patients walking ability Patients ability to work/perform activities of daily living Patients relationships with others Patients enjoyment of life Assessments are rated on a 7-point scale, in which 1 is very much worsened and 7 is very much improved since the start of the study.
Time Frame	Week 4 of the Double-blind Treatment Period

Outcome Measure Data

Analysis Population Description

FAS of participants with assessments at the timeframe

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	110	105
General Activities: Very much worsened	0 0%	0 0%
General Activities: Much worsened	1 0.7%	1 0.7%
General Activities: Slightly worsened	8 5.4%	3 2.1%
General Activities: Unchanged	31 20.9%	23 15.8%
General Activities: Slightly improved	33 22.3%	38 26%
General Activities: Much improved	31 20.9%	29 19.9%
General Activities: Very much improved	6 4.1%	11 7.5%
Walking ability: Very much worsened	0 0%	1 0.7%
Walking ability: Much worsened	0 0%	0 0%
Walking ability: Slightly worsened	8 5.4%	3 2.1%
Walking ability: Unchanged	35 23.6%	27 18.5%
Walking ability: Slightly improved	36 24.3%	36 24.7%
Walking ability: Much improved	26 17.6%	28 19.2%
Walking ability: Very much improved	5 3.4%	10 6.8%
Daily living: Very much worsened	0 0%	0 0%
Daily living: Much worsened	0 0%	2 1.4%
Daily living: Slightly worsened	6 4.1%	3 2.1%
Daily living: Unchanged	36 24.3%	24 16.4%
Daily living: Slightly improved	32 21.6%	39 26.7%
Daily living: Much improved	29 19.6%	29 19.9%
Daily living: Very much improved	7 4.7%	8 5.5%
Relationships: Very much worsened	0 0%	0 0%
Relationships: Much worsened	0 0%	1 0.7%
Relationships: Slightly worsened	3 2%	1 0.7%
Relationships: Unchanged	72 48.6%	60 41.1%
Relationships: Slightly improved	13 8.8%	18 12.3%
Relationships: Much improved	16 10.8%	18 12.3%
Relationships: Very much improved	6 4.1%	7 4.8%
Enjoyment: Very much worsened	0 0%	1 0.7%
Enjoyment: Much worsened	0 0%	0 0%
Enjoyment: Slightly worsened	8 5.4%	2 1.4%
Enjoyment: Unchanged	48 32.4%	39 26.7%
Enjoyment: Slightly improved	26 17.6%	26 17.8%
Enjoyment: Much improved	19 12.8%	28 19.2%
Enjoyment: Very much improved	9 6.1%	9 6.2%

9. Secondary Outcome

Title	Clinician Assessment of Patient Function (CAPF) at Week 8
Description	Clinicians assessed participants across 5 dimensions: Patients general activities Patients walking ability Patients ability to work/perform activities of daily living Patients relationships with others Patients enjoyment of life Assessments are rated on a 7-point scale, in which 1 is very much worsened and 7 is very much improved since the start of the study.
Time Frame	Week 8 of the Double-blind Treatment Period

Outcome Measure Data

Analysis Population Description

FAS of participants with assessments at the timeframe

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	98	91
General Activities: Very much worsened	0 0%	1 0.7%
General Activities: Much worsened	1 0.7%	1 0.7%
General Activities: Slightly worsened	6 4.1%	2 1.4%
General Activities: Unchanged	34 23%	23 15.8%
General Activities: Slightly improved	21 14.2%	24 16.4%
General Activities: Much improved	27 18.2%	32 21.9%
General Activities: Very much improved	9 6.1%	8 5.5%
Walking ability: Very much worsened	0 0%	1 0.7%
Walking ability: Much worsened	2 1.4%	1 0.7%
Walking ability: Slightly worsened	5 3.4%	1 0.7%
Walking ability: Unchanged	41 27.7%	30 20.5%
Walking ability: Slightly improved	19 12.8%	26 17.8%
Walking ability: Much improved	24 16.2%	26 17.8%
Walking ability: Very much improved	7 4.7%	6 4.1%
Daily living: Very much worsened	0 0%	2 1.4%
Daily living: Much worsened	1 0.7%	1 0.7%
Daily living: Slightly worsened	7 4.7%	0 0%
Daily living: Unchanged	38 25.7%	25 17.1%
Daily living: Slightly improved	22 14.9%	35 24%
Daily living: Much improved	24 16.2%	21 14.4%
Daily living: Very much improved	6 4.1%	7 4.8%
Relationships: Very much worsened	0 0%	0 0%
Relationships: Much worsened	0 0%	0 0%
Relationships: Slightly worsened	1 0.7%	2 1.4%
Relationships: Unchanged	68 45.9%	49 33.6%
Relationships: Slightly improved	12 8.1%	19 13%
Relationships: Much improved	16 10.8%	17 11.6%
Relationships: Very much improved	3 2%	4 2.7%
Enjoyment: Very much worsened	1 0.7%	0 0%
Enjoyment: Much worsened	0 0%	0 0%
Enjoyment: Slightly worsened	7 4.7%	1 0.7%
Enjoyment: Unchanged	38 25.7%	38 26%
Enjoyment: Slightly improved	19 12.8%	20 13.7%
Enjoyment: Much improved	27 18.2%	25 17.1%
Enjoyment: Very much improved	6 4.1%	7 4.8%

10. Secondary Outcome

Title	Clinician Assessment of Patient Function (CAPF) at Week 12
Description	Clinicians assessed participants across 5 dimensions: Patients general activities Patients walking ability Patients ability to work/perform activities of daily living Patients relationships with others Patients enjoyment of life Assessments are rated on a 7-point scale, in which 1 is very much worsened and 7 is very much improved since the start of the study.
Time Frame	Week 12 of the Double-blind Treatment Period

Outcome Measure Data

Analysis Population Description

FAS of participants with assessments at the timeframe

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	92	86
General Activities: Very much worsened	0 0%	0 0%
General Activities: Much worsened	0 0%	3 2.1%
General Activities: Slightly worsened	4 2.7%	2 1.4%
General Activities: Unchanged	29 19.6%	20 13.7%
General Activities: Slightly improved	29 19.6%	27 18.5%
General Activities: Much improved	19 12.8%	27 18.5%
General Activities: Very much improved	11 7.4%	7 4.8%
Walking ability: Very much worsened	0 0%	1 0.7%
Walking ability: Much worsened	0 0%	2 1.4%
Walking ability: Slightly worsened	3 2%	3 2.1%
Walking ability: Unchanged	38 25.7%	24 16.4%
Walking ability: Slightly improved	26 17.6%	24 16.4%
Walking ability: Much improved	18 12.2%	27 18.5%
Walking ability: Very much improved	7 4.7%	5 3.4%
Daily living: Very much worsened	0 0%	0 0%
Daily living: Much worsened	0 0%	3 2.1%
Daily living: Slightly worsened	6 4.1%	1 0.7%
Daily living: Unchanged	30 20.3%	28 19.2%
Daily living: Slightly improved	26 17.6%	22 15.1%
Daily living: Much improved	20 13.5%	26 17.8%
Daily living: Very much improved	10 6.8%	6 4.1%
Relationships: Very much worsened	0 0%	0 0%
Relationships: Much worsened	0 0%	0 0%
Relationships: Slightly worsened	1 0.7%	1 0.7%
Relationships: Unchanged	59 39.9%	47 32.2%
Relationships: Slightly improved	13 8.8%	18 12.3%
Relationships: Much improved	15 10.1%	14 9.6%
Relationships: Very much improved	4 2.7%	6 4.1%
Enjoyment: Very much worsened	0 0%	0 0%
Enjoyment: Much worsened	0 0%	2 1.4%
Enjoyment: Slightly worsened	5 3.4%	3 2.1%
Enjoyment: Unchanged	42 28.4%	31 21.2%
Enjoyment: Slightly improved	16 10.8%	23 15.8%
Enjoyment: Much improved	21 14.2%	21 14.4%
Enjoyment: Very much improved	8 5.4%	6 4.1%

11. Secondary Outcome

Title	Clinician Assessment of Patient Function (CAPF) at Endpoint
Description	Clinicians assessed participants across 5 dimensions: Patients general activities Patients walking ability Patients ability to work/perform activities of daily living Patients relationships with others Patients enjoyment of life Assessments are rated on a 7-point scale, in which 1 is very much worsened and 7 is very much improved since the start of the study. Endpoint values are the last observed postbaseline data.
Time Frame	Endpoint of the Double-blind Treatment Period (up to week 12)

Outcome Measure Data

Analysis Population Description

FAS of participants with assessments at the timeframe

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	131	132
General Activities: Very much worsened	1 0.7%	0 0%
General Activities: Much worsened	4 2.7%	5 3.4%
General Activities: Slightly worsened	9 6.1%	4 2.7%
General Activities: Unchanged	46 31.1%	38 26%
General Activities: Slightly improved	36 24.3%	37 25.3%
General Activities: Much improved	24 16.2%	40 27.4%
General Activities: Very much improved	11 7.4%	8 5.5%
Walking ability: Very much worsened	1 0.7%	1 0.7%
Walking ability: Much worsened	2 1.4%	4 2.7%
Walking ability: Slightly worsened	7 4.7%	5 3.4%
Walking ability: Unchanged	59 39.9%	45 30.8%
Walking ability: Slightly improved	34 23%	32 21.9%
Walking ability: Much improved	21 14.2%	19 13%
Walking ability: Very much improved	7 4.7%	6 4.1%
Daily living: Very much worsened	1 0.7%	0 0%
Daily living: Much worsened	4 2.7%	6 4.1%
Daily living: Slightly worsened	10 6.8%	3 2.1%
Daily living: Unchanged	49 33.1%	46 31.5%
Daily living: Slightly improved	33 22.3%	33 22.6%
Daily living: Much improved	24 16.2%	36 24.7%
Daily living: Very much improved	10 6.8%	8 5.5%
Relationships: Very much worsened	0 0%	0 0%
Relationships: Much worsened	1 0.7%	2 1.4%
Relationships: Slightly worsened	3 2%	4 2.7%
Relationships: Unchanged	90 60.8%	78 53.4%
Relationships: Slightly improved	15 10.1%	26 17.8%
Relationships: Much improved	18 12.2%	15 10.3%
Relationships: Very much improved	4 2.7%	7 4.8%
Enjoyment: Very much worsened	1 0.7%	0 0%
Enjoyment: Much worsened	2 1.4%	5 3.4%
Enjoyment: Slightly worsened	9 6.1%	5 3.4%
Enjoyment: Unchanged	66 44.6%	57 39%
Enjoyment: Slightly improved	20 13.5%	31 21.2%
Enjoyment: Much improved	25 16.9%	27 18.5%
Enjoyment: Very much improved	8 5.4%	7 4.8%

12. Secondary Outcome

Title	Patient Assessment of Function (PAF) at Week 4
Description	The PAF is a self-administered questionnaire used to measure patients' assessment of their own ability to function in normal activities. Answers to the 7 questions were rated on a 7 point scale in which 1 was very much worsened and 7 were very much improved since the start of the study. The seven functional areas are: ability to go to work ability to perform at work (includes both work outside the home and housework) ability to walk ability to exercise ability to participate in social events ability to have sex ability to enjoy life
Time Frame	Week 4 of the Double-blind Treatment Period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Go to Work: Very much worsened	0 0%	1 0.7%
Go to Work: Much worsened	2 1.4%	2 1.4%
Go to Work: Slightly worsened	8 5.4%	1 0.7%
Go to Work: Unchanged	34 23%	25 17.1%
Go to Work: Slightly improved	13 8.8%	17 11.6%
Go to Work: Much improved	12 8.1%	19 13%
Go to Work: Very much improved	6 4.1%	8 5.5%
Perform Work: Very much worsened	0 0%	1 0.7%
Perform Work: Much worsened	3 2%	4 2.7%
Perform Work: Slightly worsened	11 7.4%	0 0%
Perform Work: Unchanged	33 22.3%	20 13.7%
Perform Work: Slightly improved	32 21.6%	38 26%
Perform Work: Much improved	22 14.9%	31 21.2%
Perform Work: Very much improved	7 4.7%	9 6.2%
Walk: Very much worsened	0 0%	0 0%
Walk: Much worsened	0 0%	1 0.7%
Walk: Slightly worsened	7 4.7%	5 3.4%
Walk: Unchanged	37 25%	24 16.4%
Walk: Slightly improved	32 21.6%	34 23.3%
Walk: Much improved	27 18.2%	30 20.5%
Walk: Very much improved	6 4.1%	10 6.8%
Exercise: Very much worsened	1 0.7%	2 1.4%
Exercise: Much worsened	4 2.7%	2 1.4%
Exercise: Slightly worsened	6 4.1%	2 1.4%
Exercise: Unchanged	46 31.1%	31 21.2%
Exercise: Slightly improved	30 20.3%	39 26.7%
Exercise: Much improved	18 12.2%	20 13.7%
Exercise: Very much improved	4 2.7%	8 5.5%
Social events: Very much worsened	1 0.7%	0 0%
Social events: Much worsened	0 0%	1 0.7%
Social events: Slightly worsened	8 5.4%	3 2.1%
Social events: Unchanged	52 35.1%	37 25.3%
Social events: Slightly improved	26 17.6%	28 19.2%
Social events: Much improved	14 9.5%	22 15.1%
Social events: Very much improved	8 5.4%	13 8.9%
Sex: Very much worsened	1 0.7%	2 1.4%
Sex: Much worsened	5 3.4%	2 1.4%
Sex: Slightly worsened	8 5.4%	4 2.7%
Sex: Unchanged	66 44.6%	64 43.8%
Sex: Slightly improved	18 12.2%	7 4.8%
Sex: Much improved	5 3.4%	15 10.3%
Sex: Very much improved	4 2.7%	7 4.8%
Enjoy life: Very much worsened	1 0.7%	0 0%
Enjoy life: Much worsened	0 0%	2 1.4%
Enjoy life: Slightly worsened	8 5.4%	4 2.7%
Enjoy life: Unchanged	41 27.7%	34 23.3%
Enjoy life: Slightly improved	28 18.9%	27 18.5%
Enjoy life: Much improved	20 13.5%	28 19.2%
Enjoy life: Very much improved	11 7.4%	9 6.2%

13. Secondary Outcome

Title	Patient Assessment of Function (PAF) at Week 8
Description	The PAF is a self-administered questionnaire used to measure patients' assessment of their own ability to function in normal activities. Answers to the 7 questions were rated on a 7 point scale in which 1 was very much worsened and 7 were very much improved since the start of the study. The seven functional areas are: ability to go to work ability to perform at work (includes both work outside the home and housework) ability to walk ability to exercise ability to participate in social events ability to have sex ability to enjoy life
Time Frame	Week 8 of the Double-blind Treatment Period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Go to Work: Very much worsened	0 0%	2 1.4%
Go to Work: Much worsened	0 0%	0 0%
Go to Work: Slightly worsened	7 4.7%	3 2.1%
Go to Work: Unchanged	31 20.9%	29 19.9%
Go to Work: Slightly improved	10 6.8%	9 6.2%
Go to Work: Much improved	14 9.5%	18 12.3%
Go to Work: Very much improved	3 2%	3 2.1%
Perform Work: Very much worsened	1 0.7%	2 1.4%
Perform Work: Much worsened	3 2%	0 0%
Perform Work: Slightly worsened	7 4.7%	6 4.1%
Perform Work: Unchanged	38 25.7%	22 15.1%
Perform Work: Slightly improved	22 14.9%	25 17.1%
Perform Work: Much improved	17 11.5%	33 22.6%
Perform Work: Very much improved	9 6.1%	5 3.4%
Walk: Very much worsened	0 0%	1 0.7%
Walk: Much worsened	2 1.4%	2 1.4%
Walk: Slightly worsened	7 4.7%	4 2.7%
Walk: Unchanged	40 27%	22 15.1%
Walk: Slightly improved	23 15.5%	27 18.5%
Walk: Much improved	17 11.5%	27 18.5%
Walk: Very much improved	9 6.1%	10 6.8%
Exercise: Very much worsened	0 0%	2 1.4%
Exercise: Much worsened	3 2%	1 0.7%
Exercise: Slightly worsened	8 5.4%	8 5.5%
Exercise: Unchanged	42 28.4%	28 19.2%
Exercise: Slightly improved	23 15.5%	28 19.2%
Exercise: Much improved	16 10.8%	21 14.4%
Exercise: Very much improved	6 4.1%	5 3.4%
Social events: Very much worsened	1 0.7%	0 0%
Social events: Much worsened	1 0.7%	2 1.4%
Social events: Slightly worsened	3 2%	2 1.4%
Social events: Unchanged	48 32.4%	42 28.8%
Social events: Slightly improved	18 12.2%	19 13%
Social events: Much improved	18 12.2%	19 13%
Social events: Very much improved	9 6.1%	9 6.2%
Sex: Very much worsened	0 0%	1 0.7%
Sex: Much worsened	1 0.7%	0 0%
Sex: Slightly worsened	3 2%	9 6.2%
Sex: Unchanged	74 50%	52 35.6%
Sex: Slightly improved	9 6.1%	12 8.2%
Sex: Much improved	4 2.7%	14 9.6%
Sex: Very much improved	4 2.7%	3 2.1%
Enjoy life: Very much worsened	1 0.7%	0 0%
Enjoy life: Much worsened	1 0.7%	1 0.7%
Enjoy life: Slightly worsened	6 4.1%	3 2.1%
Enjoy life: Unchanged	41 27.7%	34 23.3%
Enjoy life: Slightly improved	24 16.2%	25 17.1%
Enjoy life: Much improved	23 15.5%	23 15.8%
Enjoy life: Very much improved	3 2%	7 4.8%

14. Secondary Outcome

Title	Patient Assessment of Function (PAF) at Week 12
Description	The PAF is a self-administered questionnaire used to measure patients' assessment of their own ability to function in normal activities. Answers to the 7 questions were rated on a 7 point scale in which 1 was very much worsened and 7 were very much improved since the start of the study. The seven functional areas are: ability to go to work ability to perform at work (includes both work outside the home and housework) ability to walk ability to exercise ability to participate in social events ability to have sex ability to enjoy life
Time Frame	Week 12 of the Double-blind Treatment Period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Go to Work: Very much worsened	0 0%	1 0.7%
Go to Work: Much worsened	2 1.4%	1 0.7%
Go to Work: Slightly worsened	5 3.4%	3 2.1%
Go to Work: Unchanged	27 18.2%	19 13%
Go to Work: Slightly improved	7 4.7%	18 12.3%
Go to Work: Much improved	13 8.8%	17 11.6%
Go to Work: Very much improved	6 4.1%	2 1.4%
Perform Work: Very much worsened	1 0.7%	1 0.7%
Perform Work: Much worsened	0 0%	3 2.1%
Perform Work: Slightly worsened	10 6.8%	5 3.4%
Perform Work: Unchanged	26 17.6%	20 13.7%
Perform Work: Slightly improved	26 17.6%	26 17.8%
Perform Work: Much improved	21 14.2%	25 17.1%
Perform Work: Very much improved	7 4.7%	4 2.7%
Walk: Very much worsened	1 0.7%	1 0.7%
Walk: Much worsened	2 1.4%	2 1.4%
Walk: Slightly worsened	10 6.8%	5 3.4%
Walk: Unchanged	29 19.6%	20 13.7%
Walk: Slightly improved	20 13.5%	27 18.5%
Walk: Much improved	23 15.5%	23 15.8%
Walk: Very much improved	6 4.1%	7 4.8%
Exercise: Very much worsened	2 1.4%	1 0.7%
Exercise: Much worsened	2 1.4%	3 2.1%
Exercise: Slightly worsened	9 6.1%	4 2.7%
Exercise: Unchanged	34 23%	30 20.5%
Exercise: Slightly improved	23 15.5%	26 17.8%
Exercise: Much improved	15 10.1%	14 9.6%
Exercise: Very much improved	6 4.1%	7 4.8%
Social events: Very much worsened	1 0.7%	0 0%
Social events: Much worsened	0 0%	2 1.4%
Social events: Slightly worsened	7 4.7%	6 4.1%
Social events: Unchanged	45 30.4%	29 19.9%
Social events: Slightly improved	16 10.8%	25 17.1%
Social events: Much improved	17 11.5%	16 11%
Social events: Very much improved	5 3.4%	7 4.8%
Sex: Very much worsened	2 1.4%	0 0%
Sex: Much worsened	2 1.4%	4 2.7%
Sex: Slightly worsened	7 4.7%	7 4.8%
Sex: Unchanged	64 43.2%	46 31.5%
Sex: Slightly improved	7 4.7%	11 7.5%
Sex: Much improved	6 4.1%	12 8.2%
Sex: Very much improved	3 2%	2 1.4%
Enjoy life: Very much worsened	1 0.7%	0 0%
Enjoy life: Much worsened	0 0%	4 2.7%
Enjoy life: Slightly worsened	7 4.7%	4 2.7%
Enjoy life: Unchanged	36 24.3%	27 18.5%
Enjoy life: Slightly improved	21 14.2%	18 12.3%
Enjoy life: Much improved	18 12.2%	24 16.4%
Enjoy life: Very much improved	8 5.4%	8 5.5%

15. Secondary Outcome

Title	Patient Assessment of Function (PAF) at Endpoint
Description	The PAF is a self-administered questionnaire used to measure patients' assessment of their own ability to function in normal activities. Answers to the 7 questions were rated on a 7 point scale in which 1 was very much worsened and 7 were very much improved since the start of the study. The seven functional areas are: ability to go to work ability to perform at work (includes both work outside the home and housework) ability to walk ability to exercise ability to participate in social events ability to have sex ability to enjoy life Endpoint values are the last observed postbaseline data.
Time Frame	Endpoint of the Double-blind Treatment Period (up to week 12)

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Go to Work: Very much worsened	0 0%	1 0.7%
Go to Work: Much worsened	4 2.7%	2 1.4%
Go to Work: Slightly worsened	10 6.8%	6 4.1%
Go to Work: Unchanged	47 31.8%	39 26.7%
Go to Work: Slightly improved	11 7.4%	26 17.8%
Go to Work: Much improved	21 14.2%	26 17.8%
Go to Work: Very much improved	6 4.1%	6 4.1%
Perform Work: Very much worsened	2 1.4%	2 1.4%
Perform Work: Much worsened	3 2%	5 3.4%
Perform Work: Slightly worsened	17 11.5%	12 8.2%
Perform Work: Unchanged	43 29.1%	34 23.3%
Perform Work: Slightly improved	31 20.9%	39 26.7%
Perform Work: Much improved	27 18.2%	34 23.3%
Perform Work: Very much improved	8 5.4%	7 4.8%
Walk: Very much worsened	1 0.7%	1 0.7%
Walk: Much worsened	7 4.7%	4 2.7%
Walk: Slightly worsened	13 8.8%	10 6.8%
Walk: Unchanged	47 31.8%	36 24.7%
Walk: Slightly improved	28 18.9%	40 27.4%
Walk: Much improved	28 18.9%	32 21.9%
Walk: Very much improved	7 4.7%	10 6.8%
Exercise: Very much worsened	4 2.7%	3 2.1%
Exercise: Much worsened	6 4.1%	5 3.4%
Exercise: Slightly worsened	13 8.8%	9 6.2%
Exercise: Unchanged	52 35.1%	51 34.9%
Exercise: Slightly improved	30 20.3%	30 20.5%
Exercise: Much improved	19 12.8%	24 16.4%
Exercise: Very much improved	7 4.7%	9 6.2%
Social events: Very much worsened	1 0.7%	1 0.7%
Social events: Much worsened	3 2%	4 2.7%
Social events: Slightly worsened	10 6.8%	12 8.2%
Social events: Unchanged	67 45.3%	51 34.9%
Social events: Slightly improved	23 15.5%	30 20.5%
Social events: Much improved	21 14.2%	25 17.1%
Social events: Very much improved	6 4.1%	10 6.8%
Sex: Very much worsened	3 2%	0 0%
Sex: Much worsened	6 4.1%	6 4.1%
Sex: Slightly worsened	10 6.8%	12 8.2%
Sex: Unchanged	88 59.5%	76 52.1%
Sex: Slightly improved	12 8.1%	13 8.9%
Sex: Much improved	8 5.4%	18 12.3%
Sex: Very much improved	4 2.7%	4 2.7%
Enjoy life: Very much worsened	2 1.4%	0 0%
Enjoy life: Much worsened	3 2%	7 4.8%
Enjoy life: Slightly worsened	10 6.8%	9 6.2%
Enjoy life: Unchanged	59 39.9%	45 30.8%
Enjoy life: Slightly improved	27 18.2%	25 17.1%
Enjoy life: Much improved	21 14.2%	35 24%
Enjoy life: Very much improved	9 6.1%	11 7.5%

16. Secondary Outcome

Title	Clinician Global Impression of Severity (CGI-S) of Illness Scores During the Double-blind Treatment Period
Description	The CGI-S is a clinician-rated scale that assesses the severity of the patient's pain condition and response to the treatment. Severity of illness, as related to moderate to severe pain, consists of the following 7 categories: 1 normal-shows no sign of illness, 2 borderline ill, 3 mildly (slightly) ill, 4 moderately ill, 5 markedly ill, 6 severely ill, and 7 among the most extremely ill (Guy 1976). The clinician assesses the severity of the patient's condition, based on the clinician's total clinical experience with patients with this condition, in response to treatment. Endpoint values are the last observed postbaseline data.
Time Frame	Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, and 12 of the Double-blind treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Baseline	3.0 (1.19)	2.8 (1.07)
Week 1	2.9 (1.16)	2.9 (1.10)
Week 2	2.9 (1.20)	2.8 (1.07)
Week 4	2.9 (1.26)	2.7 (1.03)
Week 8	2.8 (1.21)	2.7 (1.01)
Week 12	2.8 (1.19)	2.7 (1.08)
Endpoint	2.9 (1.18)	2.8 (1.12)

17. Secondary Outcome

Title	Short-Form Health Survey (SF-36) Physical and Mental Component Summary Scores at Baseline, Week 12 and Endpoint
Description	SF-36 is a generic 36-item questionnaire measuring health-related quality of life (HRQL) covering 2 summary measures: physical component summary (PCS) and mental component summary (MCS). The SF-36 consists of 8 subscales. The PCS is represented by 4 subscales: physical function, role limitations due to physical problems, pain, and general health perception. The MCS is represented by 4 subscales: vitality, social function, role limitations due to emotional problems, and mental health. Participants self-report on items in a subscale that have between 2-6 choices per item using Likert-type responses (e.g. none of the time, some of the time, etc.). PCS and MCS scores are constructed as a T-score with a mean of 50 and standard deviation of 10 and no minimum or maximum score; higher scores indicate better health status.
Time Frame	Baseline (end of Open-Label Titration Period), Week 12 and Endpoint (last visit up to week 12) of the Double-blind treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
PCS - Baseline	35.5 (8.96)	35.8 (9.28)
PCS - Week 12	36.9 (10.04)	37.6 (9.04)
PCS - Endpoint	35.9 (10.13)	36.9 (9.16)
MCS - Baseline	52.8 (9.99)	52.8 (10.47)
MCS - Week 12	54.7 (9.71)	53.6 (8.06)
MCS - Endpoint	54.0 (10.27)	52.6 (9.22)

18. Secondary Outcome

Title	Brief Pain Inventory - Short Form (BPI-SF) Pain Interference Mean Score During the Double-Blind Treatment Period
Description	For pain interference, the BPI-SF used numerical scales to measure how much pain had interfered with 7 daily activities, including general activity, walking, work, mood, enjoyment of life, relations with others, and sleep in the past 24 hours. The scale used an 11 point Likert scale; range: 0 [does not interfere] to 10 [completely interferes]. BPI pain interference was typically scored as the mean of the 7 interference items. This mean could be used if at least 4 of 7 items had been completed on a given administration.
Time Frame	Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, 12 and Endpoint (last visit up to week 12) of the Double-blind treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered ER hydrocodone tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Baseline	2.9 (2.09)	2.8 (2.05)
Week 1	3.0 (2.23)	3.1 (2.22)
Week 2	2.9 (2.25)	2.7 (2.19)
Week 4	2.9 (2.39)	2.8 (2.06)
Week 8	2.9 (2.37)	2.9 (2.23)
Week 12	3.0 (2.31)	3.3 (2.30)
Endpoint	3.5 (2.45)	3.3 (2.28)

19. Secondary Outcome

Title	Participants With Adverse Events
Description	An adverse event (AE) was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time Frame	Day 1 up to Day 52 in Open-Label Titration; Day 1 up to Day 128 in Double-Blind Treatment period

Outcome Measure Data

Analysis Population Description

Safety analysis set (Open-Label Titration) and FAS (Double-Blind Treatment)

Arm/Group Title	Open-Label Titration: Opioid Naive	Open-Label Titration: Opioid Experienced	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	During the open label titration period, all participants received hydrocodone extended release tablets on an open-label basis. Opioid naïve participants (ie, those taking less than 10 mg/day of oxycodone or equivalent, during the 14 days before screening) started at a 15 mg dose of hydrocodone extended release, administered every 12 hours. A decision regarding dose adjustment was made based on whether the criterion of successful dose (ie, dose that produced stable pain relief) was met. In general, dose escalation stepped from 15 mg to 30 mg, 45 mg, 60 mg, and 90 mg every 12 hours until stable pain relief was obtained.	During the open label titration period, all participants received hydrocodone extended release tablets on an open-label basis. Opioid experienced participants switched from their current opioid medications to the calculated dose of hydrocodone extended release tablets based on an equianalgesic dose-conversion scheme. A decision regarding dose adjustment was made based on whether the criterion of successful dose (ie, dose that produced stable pain relief) was met. In general, dose escalation stepped to 30 mg or 45 mg or 60 mg, or 90 mg every 12 hours until stable pain relief was obtained. The escalated dose was dependent upon the initial calculated equivalent dose.	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	189	200	147	146
Any adverse event	111 75%	116 79.5%	91 31%	93 NaN
Severe adverse event	9 6.1%	8 5.5%	7 2.4%	9 NaN
Treatment-related adverse event	90 60.8%	72 49.3%	28 9.5%	48 NaN
Deaths	0 0%	0 0%	0 0%	0 NaN
Serious adverse event	0 0%	2 1.4%	3 1%	3 NaN
Withdrawals from treatment due to AE	33 22.3%	15 10.3%	3 1%	9 NaN

20. Secondary Outcome

Title	Participants With Potentially Clinically Significant Abnormal Vital Signs Values During the Double-Blind Treatment Period
Description	Data represents participants with potentially clinically significant (PCS) vital sign values. Significance criteria Pulse - high: >=120 and increase of >= 15 beats/minute from baseline Pulse - low: <=50 and decrease of >=15 beats/minute Systolic blood pressure - high: >=180 and increase >=20 mmHg Systolic blood pressure - low: <=90 and decrease >=20 mmHg Diastolic blood pressure - high: >=105 and increase of >=15 mmHg Diastolic blood pressure - low: <=50 and decrease of >=15 mmHg
Time Frame	Day 1 up to Day 128 in Double-Blind Treatment period

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
At least one clinically significant vital sign	2 1.4%	5 3.4%
Pulse - high	0 0%	0 0%
Pulse - low	0 0%	0 0%
Systolic blood pressure - high	1 0.7%	0 0%
Systolic blood pressure - low	1 0.7%	3 2.1%
Diastolic blood pressure - high	0 0%	2 1.4%
Diastolic blood pressure - low	0 0%	1 0.7%

21. Secondary Outcome

Title	Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period
Description	Data represents participants with potentially clinically significant abnormal serum chemistry, hematology and urinalysis values. Significance criteria: Blood urea nitrogen: >=10.71 mmol/L Uric acid: M>=625, F>=506 μmol/L Hemoglobin: M<=115, F<=95 g/dL Hematocrit: M<0.37, F<0.32 % Urinalysis: blood (hemoglobin) and total protein: >=2 unit increase from baseline
Time Frame	Day 1 up to Day 128 in Double-Blind Treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set including participants with laboratory assessments

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Blood urea nitrogen	1 0.7%	4 2.7%
Uric acid	2 1.4%	5 3.4%
Hemoglobin	1 0.7%	3 2.1%
Hematocrit	1 0.7%	5 3.4%
Urine blood	2 1.4%	3 2.1%
Urine total protein	1 0.7%	0 0%

22. Secondary Outcome

Title	Subjective Opiate Withdrawal Scales (SOWS) Scores During the Double-Blind Treatment Period
Description	The results of the SOWS were collected in the e-diary daily during the first 4 weeks of the double blind treatment period and then during clinic visits at weeks 8 and 12 or early termination. The SOWS was a self administered questionnaire used to measure a participant's signs and symptoms of withdrawal from opiates. The scale contained 16 symptoms (eg, my nose is running; I feel restless), the participant rated the intensity on a scale of 0 (not at all) to 4 (extremely) for a total score of 0-64. The daily total score for the first 4 weeks was the largest score observed during the time period preceding that visit. For example, the week 1 score for each participant was the largest total score on any day between baseline and the night before the week 1 visit; the week 4 score for each participant was the largest score observed between the week 2 visit and the night before the week 4 visit.
Time Frame	Weeks 1, 2, 4, 8, 12 and Endpoint (last visit up to Week 12) of the Double-blind treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Week 1	5.9 (5.39)	6.1 (5.93)
Week 2	5.4 (5.59)	4.4 (5.10)
Week 4	5.5 (6.16)	5.3 (5.37)
Week 8	3.4 (4.68)	3.2 (4.23)
Week 12	3.2 (4.73)	3.6 (5.29)
Endpoint	3.6 (4.96)	4.3 (6.30)

23. Secondary Outcome

Title	Clinical Opiate Withdrawal Scales (COWS) Scores During the Double-Blind Treatment Period
Description	The COWS was a clinician rated scale used to measure a participant's signs and symptoms of withdrawal from opiates, with ratings based only on apparent relationship to withdrawal. The COWS was performed at day 0 and weeks 1, 2, 4, 8, and 12 (double blind treatment period) or early termination. The scale contained 11 signs/symptoms whose intensity the clinician rated on a scale of 0 to 4 or 5. A total score was calculated as the sum of the responses to the 11 signs/symptoms for a total range of 0-48. Withdrawal severity was classified, based on the total score, as follows: 0 to 4=normal 5 to 12=mild 13 to 24=moderate 25 to 36=moderately severe >36=severe
Time Frame	Baseline (end of Open-Label Titration Period), Weeks 1, 2, 4, 8, 12 and Endpoint (last visit up to Week 12) of the Double-blind treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Baseline	0.5 (0.90)	0.5 (0.90)
Week 1	0.8 (1.51)	0.7 (1.29)
Week 2	0.7 (1.33)	0.5 (0.92)
Week 4	0.8 (1.58)	0.6 (1.22)
Week 8	0.7 (1.34)	0.6 (1.15)
Week 12	0.5 (0.92)	0.8 (1.76)
Endpoint	0.7 (1.13)	1.1 (2.02)

24. Secondary Outcome

Title	Addiction Behavior Checklist (ABC) Total Scores During Both the Open-Label Titration and Double-Blind Treatment Periods
Description	The ABC was a clinician rated scale that consisted of a brief (20 item) questionnaire designed to track behaviors characteristic of addiction related to prescription opioid medications in chronic pain populations. Items were focused on observable behaviors noted both during and between clinic visits. Each affirmative response was counted as one point, and points were added to calculate the total score, consequently resulting in scores ranging from 0 to 20 (0=no addiction-related behaviors seen and higher scores indicating an increasing number of addition-related behaviors seen). The ABC was to be performed at visits 2 and 7 (beginning and end of Open-label Titration period) and weeks 1, 4, 8, and 12 (Double-blind Treatment period) or early termination.
Time Frame	Baseline for Open-Label Titration period, Baseline for Double-Blind Treatment period (which is also the end of the Open-Label Titration period), Weeks 1, 4, 8, 12, and Endpoint (last visit up to Week 12) of the Double-blind Treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Baseline Open-Label Titration	0.3 (0.65)	0.3 (0.70)
Baseline Double-blind Treatment	0.1 (0.39)	0.2 (0.43)
Week 1	0.2 (0.47)	0.2 (0.50)
Week 4	0.1 (0.40)	0.3 (0.70)
Week 8	0.1 (0.36)	0.2 (0.47)
Week 12	0.1 (0.38)	0.1 (0.38)
Endpoint	0.3 (0.75)	0.3 (0.73)

25. Secondary Outcome

Title	Current Opioid Misuse Measures (COMM) Total Scores During Both the Open-Label Titration and Double-Blind Treatment Periods
Description	The COMM was a clinician rated scale developed as a brief self report measure of current aberrant drug-related behavior for patients with chronic pain who were already on long term opioid therapy. A total score was calculated as the sum of the 17 questions. The total score ranged from 0 to 68. A score of 0 indicates no aberrant drug-related behaviors were seen. Patients with a total score of 9 or greater were classified as exhibiting aberrant drug-related behavior. The COMM was to be performed at visits 2 and 7 (beginning and end of Open-label Titration period) and weeks 1, 4, 8, and 12 (Double-blind Treatment period) or early termination.
Time Frame	Baseline for Open-Label Titration period, Baseline for Double-Blind Treatment period (which is also the end of the Open-Label Titration period), Weeks 1, 4, 8, 12, and Endpoint (last visit up to Week 12) of the Double-blind Treatment period

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants contributing to each time point are included in the number analyzed.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	147	146
Baseline Open-Label Titration	3.7 (4.10)	4.2 (4.14)
Baseline Double-blind Treatment	3.7 (4.12)	3.9 (4.29)
Week 1	2.9 (3.70)	3.1 (3.10)
Week 4	2.4 (3.10)	2.8 (3.31)
Week 8	2.5 (3.51)	2.2 (2.87)
Week 12	2.8 (3.51)	3.0 (3.53)
Endpoint	3.0 (3.67)	3.3 (3.78)

26. Secondary Outcome

Title	Change From Baseline to Endpoint in the Double-Blind Treatment Phase in Electrocardiogram (ECG) Parameters
Description	A 12-lead ECG was conducted at baseline and the last visit during the double-blind treatment period (week 12, or early termination).
Time Frame	Baseline (end of Open-Label Titration Period), Endpoint (last visit up to Week 12) of the Double-blind treatment period

Outcome Measure Data

Analysis Population Description

FAS of participants contributing baseline and endpoint data.

Arm/Group Title	Placebo (Double-blind Treatment Period)	Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.	Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Measure Participants	146	142
PR interval	-1.8 (16.27)	-2.4 (29.30)
QRS interval	-0.1 (15.96)	0.6 (10.43)
QT interval	-3.1 (27.08)	2.2 (28.28)
QTc interval (Bazett)	-1.0 (20.34)	4.2 (22.74)
QTc interval (Fridericia)	-2.5 (21.10)	2.9 (21.70)

Adverse Events

Time Frame	Day 1 up to Day 52 in Open-Label Titration; Day 1 up to Day 128 in Double-Blind Treatment period
Arm/Group Title	Hydrocodone ER (Open-Label Titration Period)		Placebo (Double-blind Treatment Period)		Hydrocodone ER (Double-blind Treatment Period)
Arm/Group Description	All enrolled participants entered the open label titration period and received hydrocodone extended release (ER) tablets beginning with 15 mg every 12 hours for 3 to 7 days. Dosages were titrated upward until pain was effectively controlled. If an effective dosage between 15 mg - 90 mg twice a day was not identified within 6 week, the participant was withdrawn.		Participants were administered placebo tablets twice a day that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.		Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
All Cause Mortality
	Hydrocodone ER (Open-Label Titration Period)		Placebo (Double-blind Treatment Period)		Hydrocodone ER (Double-blind Treatment Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Hydrocodone ER (Open-Label Titration Period)		Placebo (Double-blind Treatment Period)		Hydrocodone ER (Double-blind Treatment Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/389 (0.5%)		3/147 (2%)		3/146 (2.1%)
Gastrointestinal disorders
Oesophagitis	0/389 (0%)	0	0/147 (0%)	0	1/146 (0.7%)	1
Pancreatitis	0/389 (0%)	0	0/147 (0%)	0	1/146 (0.7%)	2
General disorders
Hernia obstructive	0/389 (0%)	0	0/147 (0%)	0	1/146 (0.7%)	1
Immune system disorders
Anaphylactic reaction	0/389 (0%)	0	0/147 (0%)	0	1/146 (0.7%)	1
Injury, poisoning and procedural complications
Hip fracture	0/389 (0%)	0	1/147 (0.7%)	1	0/146 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/389 (0%)	0	1/147 (0.7%)	2	0/146 (0%)	0
Bladder cancer recurrent	0/389 (0%)	0	1/147 (0.7%)	1	0/146 (0%)	0
Renal and urinary disorders
Renal failure acute	1/389 (0.3%)	1	0/147 (0%)	0	0/146 (0%)	0
Vascular disorders
Deep vein thrombosis	1/389 (0.3%)	1	0/147 (0%)	0	0/146 (0%)	0
Other (Not Including Serious) Adverse Events
	Hydrocodone ER (Open-Label Titration Period)		Placebo (Double-blind Treatment Period)		Hydrocodone ER (Double-blind Treatment Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	167/389 (42.9%)		24/147 (16.3%)		45/146 (30.8%)
Gastrointestinal disorders
Constipation	55/389 (14.1%)	61	7/147 (4.8%)	8	19/146 (13%)	19
Nausea	70/389 (18%)	75	9/147 (6.1%)	11	19/146 (13%)	20
Vomiting	25/389 (6.4%)	26	5/147 (3.4%)	6	9/146 (6.2%)	9
Nervous system disorders
Dizziness	22/389 (5.7%)	23	1/147 (0.7%)	1	3/146 (2.1%)	3
Headache	43/389 (11.1%)	50	8/147 (5.4%)	8	10/146 (6.8%)	13
Somnolence	45/389 (11.6%)	51	1/147 (0.7%)	1	3/146 (2.1%)	3
Skin and subcutaneous tissue disorders
Pruritus	20/389 (5.1%)	23	1/147 (0.7%)	1	3/146 (2.1%)	4

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

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